Fungicidal pyridyl imidates

ABSTRACT

Novel fungicidal pyridyl imidates having the general structural formula ##STR1## wherein R is selected from the group consisting of C 1  -C 16  alkyl, C 3  -C 8  cycloalkyl, C 2  -C 8  alkenyl, C 2  -C 8  substituted alkenyl, C 3  -C 4  carboalkoxyalkyl, aryl, arylalkyl having C 1  -C 3  alkyl, substituted aryl and arylalkyl wherein the substituents are --Cl, --Br, --F and --NO 2 , furfuryl pyridyl, C 1  -C 6  alkyl substituted phosphorus, and ##STR2## wherein R 3  and R 4  are C 1  -C 10  alkyl and can form a heterocyclic ring, R 1  is selected from the group consisting of halogen, C 1  -C 3  alkoxy and C 1  -C 3  haloalkoxy, R 2  is selected from the group consisting of methyl and hydrogen, and X is S or O; and fungicidally acceptable organic and inorganic salts thereof.

This is a division of Ser. No. 036,543, filed 4/15/87, now U.S. Pat. No. 4,767,771, which is a continuation-in-part of Ser. No. 944,170, filed 12/27/86, now abandoned, which is a continuation of Ser. No. 859,153, filed 5/2/86, now abandoned.

BACKGROUND OF THE INVENTION

Fungal infection of crops such as barley, rice, tomatoes, wheat, beans, roses, grapes and other agriculturally important crops can cause heavy losses in both quantity and quality of agricultural products. It is therefore extremely desirable to have means of preventing, controlling or eliminating fungal growth. Much preventive spraying with commercial fungicides is conducted to attempt to prevent the establishment and growth of fungi on agriculturally important crops. It would also be desirable to have a curative fungicide which, on detection of fungal infestation, can destroy the fungi and eliminate the deleterious effects by use of a postinfestation curative spray.

SUMMARY OF THE INVENTION

Novel fungicidal pyridyl imidates having the formula ##STR3## wherein R is selected from the group consisting of C₁ -C₁₆ alkyl, C₃ -C₈ cycloalkyl, C₂ -C₈ alkenyl, C₂ -C₈ substituted alkenyl, C₃ -C₄ carboalkoxyalkyl, aryl, arylalkyl having C₁ -C₃ alkyl, substituted aryl and arylalkyl wherein the substituents are --Cl, --Br, --F and --NO₂, the preferred aryl and arylalkyl are phenyl, benzyl, phenethyl and naphthyl, furfuryl, pyridyl, C₁ -C₆, preferably C₁ -C₄, alkyl substituted phosphorus, and ##STR4## wherein R₃ and R₄ are C₁ -C₁₀ alkyl and can form a heterocyclic ring, R₁ is selected from the group consisting of halogen, such as chlorine, fluorine and bromine, preferably chlorine, C₁ -C₃ alkoxy such as propoxy ethoxy and methoxy, preferably methoxy and C₁ -C₃ haloalkoxy, R₂ is selected from the group consisting of methyl and hydrogen, and X is S or O; and fungicidally acceptable organic and inorganic salts thereof which are highly effective fungicides for use both as preventive and curative fungicides are disclosed herein.

The term "fungicide" is used to mean a compound which controls fungal growth. "Controls" includes prevention, destruction and inhibition of fungal growth. The term "curative" is meant to refer to a post infection application of a fungicidide which establishes control of fungal infection and prevents development of deleterious effects of the fungi on the host crop.

DETAILED DESCRIPTION

The novel fungicidal compounds of this invention are pyridyl imidates having the general formula ##STR5## wherein R is selected from the group consisting of C₁ -C₁₆ alkyl, C₃ -C₈ cycloalkyl, C₂ -C₈ alkenyl, C₂ -C₈ substituted alkenyl, C₃ -C₄ carboalkoxyalkyl, aryl, arylalkyl having C₁ -C₃ alkyl, substituted aryl and arylalkyl wherein the substituents are --Cl, --Br, --F and --NO₂, the preferred aryl and arylalkyl are phenyl, benzyl, phenethyl and naphthyl, furfuryl, pyridyl, C₁ -C₆, preferably C₁ -C₄, alkyl substituted phosphorus, and ##STR6## wherein R₃ and R₄ are C₁ -C₁₀ alkyl and can form a heterocyclic ring, R₁ is selected from the group consisting of halogen, such as chlorine, fluorine and bromine, preferably chlorine, C₁ -C₃ alkoxy such as propoxy ethoxy and methoxy, preferably methoxy and C₁ -C₃ haloalkoxy, R₂ is selected from the group consisting of methyl and hydrogen, and X is S or O; and fungicidally acceptable organic and inorganic salts thereof which are highly effective fungicides for use both as preventive and curative fungicides are disclosed herein.

The compounds of this invention can be generally prepared by reacting a novel properly substituted N-(2-substituted-5-pyridyl)cyclopropane carboximidoyl chloride having the general formula ##STR7## wherein R₁ and R₂ are as described above prepared by reacting a properly 2-substituted 5 amino pyridine with cyclopropane carboxylic acid chloride in the presence of an acid scavenger in an inert solvent such as dichloromethane. This cyclopropanecarboxamide is further reacted with phosphorus pentachloride in an inert solvent such as methylene chloride to give the carboximidoyl chloride which is then reacted with a properly substituted thiol in an inert solvent such as dichloroethane in a suitable reactor. It is desirable to maintain an acid scavenger such as pyridine in the reaction vessel. The reaction generally will proceed at room temperature but will operate at a temperature range from -20° to 80° C., depending on the thiol and the imidoyl chloride. The reaction should go to completion within 1 to 3 hours. The resulting product is recovered in a conventional manner by washing with an alkali solution such as NaOH and water, drying over conventional drying agents such as magnesium sulfate and evaporating off the solvent to give the product. Salts of the various pyridyl cyclopropane carboxythioimidates can be conventionally prepared by reacting at least a molar amount of a Lewis acid with the thioimidate. Preferably the reaction is run in a solvent for the thioimidate. The prepared salt is recovered from the reaction mixture by conventional techniques.

Pyridyl thioimidates of the invention are mildly basic. The unprotonated nitrogen atom of the pyridyl ring can be protonated by an acid, preferably either organic or inorganic. Representative inorganic acids are hydrochloric, nitric, hydrobromic, sulfuric, sulfamic and phosphoric. Representative organic acids are acetic, trifluoroacetic, benzoic, benzene-sulfonic, p-toluenesulfonic, naphthalenesulfonic, phenylphosphonic and organophosphonic. The salts so formed are also fungicidal.

EXAMPLE 1 Preparation of N-(2-Methoxy-5-pyridyl)-cyclopropane carboxamide

5-Amino-2-methoxy pyridine (12.4 grams, 0.10 mole) and 10 milliliters (ml) of pyridine were mixed together in 200 ml of dichloromethane in a reaction flask. 9.1 ml (0.10 mole) of cyclopropane carboxylic acid chloride was added to the reaction mixture over a period of 2 minutes. The reaction was exothermic and temperature rose to 34° C. The reaction was allowed to stand for one hour at room temperature, after which the reaction mixture was washed with 200 ml of 5% sodium hydroxide and 100 ml of water. The resulting organic phase was separated and dried over anhydrous magnesium sulfate. Crystals formed, so the mixture was filtered and washed with 300 ml of acetone and the filtrate evaporated in vacuo to give a solid that was triturated with hexane to yield 16.7 grams, after drying. The product was identified by IR and NMR as the title compound, having a melting point of 130°-131° C. This compound will be referred to as Compound 1.

EXAMPLE 2 Preparation of N-(2-Methoxy-5-pyridyl)-cyclopropane carboximidoyl chloride

Fifty ml dichloromethane and 10.4 g (0.05M) phosphorus pentachloride were mixed together in a reaction flask. Nine g (0.05M) of the compound of Example 1 was added, under nitrogen, in portions to the reaction flask with stirring. The reaction was exothermic and was stirred at room temperature for one hour and then heated to reflux with stirring for an additional hour to dissolve and react the solids in the reaction vessel. The reaction mixture was then evaporated under vacuum to give a solid product that was washed twice using either (50 ml portions) and dried under vacuum to yield 12.0 g of a solid, identified as the title compound by nuclear magnetic resonance spectra.

EXAMPLE 3 Preparation of N-(2-Methoxy-5-pyridyl)-S-ethyl-cyclopropane carboxthioimidate

Three grams (0.01 mole) of the compound of Example 2 and 0.74 ml (0.01 mole) ethanethiol was dissolved in 150 ml of dichloromethane in a 300 ml, one-neck, round-bottom flask by swirling. 3.0 ml triethylamine was added. The reaction mixture turned purple and then became clear over a period of one hour. The resulting solution was evaporated on a rotary evaporator, yielding an oil that was triturated with 50 ml hexane and filtered. Rotary evaporation of the hexane extract yielded 1.6 g of an oil, which was identified by nuclear magnetic resonance spectroscopy as the title compound. This compound will be known as Compound 1.

Representative compounds of this invention and their properties are shown in Table I.

                                      TABLE I                                      __________________________________________________________________________      ##STR8##                                                                      Cmpd.                            Physical Properties                           No. R                 R.sub.1                                                                             R.sub.2                                                                           X  n.sub.D.sup.30 or MP                          __________________________________________________________________________     1   CH.sub.2 CH.sub.3 OCH.sub.3                                                                           H  S  oil                                                ##STR9##         OCH.sub.3                                                                           H  S  oil                                           3                                                                                   ##STR10##        Cl   H  S                                                4   C(CH.sub.3).sub.3 OCH.sub.3                                                                           H  O                                                5                                                                                   ##STR11##        Cl   H  O                                                6   C.sub.12 H.sub.25 OCH.sub.3                                                                           H  O                                                7                                                                                   ##STR12##        OCH.sub.3                                                                           H  O                                                8                                                                                   ##STR13##        OCH.sub.3                                                                           H  S                                                9                                                                                   ##STR14##        OCH.sub.3                                                                           H  S                                                10                                                                                  ##STR15##        OCH.sub.3                                                                           H  S  129.0-134.0                                   11  hydrochloric acid salt of compound 15                                                                       155.0                                         12  hydrochloric acid salt of compound 22                                                                       128.0                                         13  CH.sub.3          Cl   H  O                                                14  CH.sub.3          OCH.sub.3                                                                           H  O                                                15  CH.sub.2 CHCH.sub.2                                                                              OCH.sub.3                                                                           H  O                                                16                                                                                  ##STR16##        OCH.sub.3                                                                           H  S                                                17                                                                                  ##STR17##        OCH.sub.3                                                                           H  S                                                18  --                OCH.sub.3                                                                           H  S                                                19                                                                                  ##STR18##        OCH.sub.3                                                                           H   S                                               20  C.sub.16 H.sub.33 OCH.sub.3                                                                           H  S                                                21  C.sub.4 H.sub.9   OCH.sub.3                                                                           H  O                                                22                                                                                  ##STR19##        OCH.sub.3                                                                           H  O                                                23                                                                                  ##STR20##        OCH.sub.3                                                                           H  O                                                24                                                                                  ##STR21##        OCH.sub.3                                                                           H  S                                                25                                                                                  ##STR22##        OCH.sub.3                                                                           H  O                                                26                                                                                  ##STR23##        OCH.sub.3                                                                           H  S                                                27                                                                                  ##STR24##        OCH.sub.3                                                                           H  S                                                28  CH.sub.2 CHCH.sub.2                                                                              OCH.sub.3                                                                           H  S                                                29                                                                                  ##STR25##        OCH.sub.3                                                                           H  S                                                30                                                                                  ##STR26##        OCH.sub.3                                                                           H  S                                                __________________________________________________________________________

EXAMPLE 4 Mole Equivalent Preventative Spray Evaluation Procedures Leaf Rust (LR)

Seven seeds of Anza wheat are planted in 2" pots in a sandy-loam soil 12 days prior to testing. The compound to be tested is diluted with a 50/50 acetone/water solution to produce concentrations decreasing from 0.004 molar. Twelve ml of test solution are sprayed onto the wheat plants with an atomizing sprayer.

A suspension of Puccinia recondita urediospores is prepared by vacuuming spores from wheat leaves with ureida pustules and suspending 10⁵ spores/ml in deionized water plus 0.5% Tween® 20 (Polyoxyethylene sorbitan monolaurate). Plants are inoculated 24 hours after treatment by spraying with the spore suspension to runoff, allowing it to dry on the leaves, respraying to runoff, and then placing the plants into a dark mist chamber. Following 48 hours in the mist, plants are moved to a subirrigation greenhouse bench.

Results are recorded ten days following inoculation as percent disease control based on the percent reduction in lesion area as compared to the untreated control plants. Compound concentrations which provide 90% disease control (EC 90) are determined from dosage/dilution curves.

Botrytis Bud Blight (BB)

Two white rose petals are placed in a petri dish lined with wet filter paper. The compound to be tested is diluted with a 50/50 acetone/water solution to produce concentrations decreasing from 0.004 molar. One half ml of test solution is atomized onto the petals, and allowed to dry.

Inoculum is prepared by adding a 5 mm plug from a two-week old Botrytis cineria culture grown on Elliot's V-8 agar, to 10 ml sterile distilled water plus 0.5% grape juice. A 20 ul drop of this inoculum suspension is placed on each petal. Petri dishes with inoculated petals are stored in sealed plastic boxes to maintain saturated humidity.

Results are read four days following inoculation as a percent reduction in necrotic area compared to the acetone/water controls. Compound concentrations which provide 90% disease control (EC 90) are determined from dosage/dilution curves.

The results are presented in Table II as an approximate EC 90 in parts per million. The entry (750) indicates partial control at 750 ppm.

                  TABLE II                                                         ______________________________________                                         Cmpd. No.         LR     BB                                                    ______________________________________                                         1                 750     80                                                   2                 750     25                                                   3                 --     250                                                   4                 --      20                                                   5                 --     750                                                   6                 --     750                                                   7                 --     250                                                   8                 --      80                                                   9                 --      30                                                   10                --     (750)                                                 11                --     (750)                                                 12                --     250                                                   13                --     750                                                   14                --     (750)                                                 15                --     250                                                   16                --      80                                                   17                --      50                                                   18                --      30                                                   19                --      40                                                   20                --     (750)                                                 21                --     (750)                                                 22                --     (750)                                                 23                --      20                                                   24                --      20                                                   25                --      35                                                   26                (750)  (750)                                                 27                --      70                                                   28                --      80                                                   29                --      30                                                   30                --     250                                                   ______________________________________                                    

EXAMPLE 5 Curative Spray Evaluation Procedures Leaf Rust (LR)

Seven seeds of Anza wheat are planted in 2" pots in a sandy loam soil 12 days prior to testing. A suspension of Puccinia recondita urediospores is prepared by vacuuming spores from wheat leaves with ureida pustules and suspending 10⁵ spores/ml in deionized water plus 0.5% Tween® 20 (polyoxyethylene sorbitan monolaurate). Plants are inoculated by spraying with the spore suspension to runoff, allowing it to dry on the leaves, respraying to runoff, and then placing the plants into a mist chamber. Following 48 hours in the mist, plants are moved to a subirrigation greenhouse bench.

The compound to be tested is diluted in a 50:50 acetone/water solution to produce concentrations decreasing from 0.075%. Fifty hours following inoculation the plants are placed on a rotating turntable and sprayed with the test solution to near runoff with atomizing nozzles. (Time of inoculation is defined as when plants are placed into the mist chamber.)

Results are recorded ten days following inoculation as percent disease control based on the percent reduction in lesion area as compared to the untreated control plants.

                  TABLE III                                                        ______________________________________                                                Cmpd. No.                                                                              LR                                                              ______________________________________                                                1       100                                                                    2       100                                                             ______________________________________                                    

The compounds of this invention are particularly effective against Botrytis bud blight and are particularly effective as preventative foliar sprays and curative foliar sprays when compared to standard commercial compounds used as Botrytis preventative and curative sprays. Another fungi on which the compounds of the present invention are particularly effective is as follows: Puccinia recondita.

The compounds of the present invention are useful as fungicides, especially as preventative or curative fungicides, and can be applied in a variety of ways at various concentrations. In general, these compounds and formulations of these compounds can be applied directly to the crop foliage, the soil in which the crop is growing or in the irrigation water for the crop or soil. In practice, the compounds herein defined are formulated into fungicidal compositions, by admixture, in fungicidally effective amounts, with the adjuvants and carriers normally employed for facilitating the dispersion of active ingredients for agricultural applications, recognizing the fact that the formulation and mode of application of a toxicant may affect the activity of the materials in a given application. Thus, these active fungicidal compounds may be formulated as wettable powders, as emulsifiable concentrates, as powdery dusts, as solutions or as any of several other known types of formulations, depending upon the desired mode of application. Preferred formulations for preventative or curative fungicidal applications are wettable powders and emulsifiable concentrates. These formulations may contain as little as about 0.5% to as much as about 95% or more by weight of active ingredient. A fungicidally effective amount depends upon the nature of the seeds or plants to be treated and the rate of application varies from about 0.05 to approximately 25 pounds per acre, preferably from about 0.1 to about 10 pounds per acre.

Wettable powders are in the form of finely divided particles which disperse readily in water or other dispersants. The wettable powder is ultimately applied to the soil or plants either as a dry dust or as a dispersion in water or other liquid. Typical carriers for wettable powders include fuller's earth, kaolin clays, silicas and other readily wet organic or inorganic diluents. Wettable powders normally are prepared to contain about 5% to about 95% of the active ingredient and usually also contain a small amount of wetting, dispersion, or emulsifying agent to facilitate wetting and dispersion.

Dry flowables or water dispersible granules are agglomerated wettable powders made by either pan granulation or by fluidized bed. The dry flowable is ultimately applied to the soil or plants as a dispersion in water or other liquid. These granules are dust-free and free flowing when dry and yet upon dilution in water, form homogeneous dispersions. Typical carriers for dry flowables include fuller's earth, kaolin clays, clays, silicas and other readily wet organic or inorganic diluents. The dry flowables normally are prepared to contain from about 5% to about 95% of the active ingredient and usually contain a small amount of wetting, dispersing or emulsifying agent to facilitate wetting and dispersion.

Emulsifiable concentrates are homogeneous liquid compositions which are dispersible in water or other dispersant, and may consist entirely of the active compound with a liquid or solid emusifying agent, or may also contain a liquid carrier, such as xylene, heavy aromatic naphtha, isophorone and other non-volatile organic solvents. For fungicidal application, these concentrates are dispersed in water or other liquid carrier and normally applied as a spray to the area to be treated. The percentage by weight of the essential active ingredient may vary according to the manner in which the composition is to be applied, but in general comprises about 0.1% to 95% of active ingredient by weight of the fungicidal composition.

Typical wetting, dispersing or emulsifying agents used in agricultural formulations include, for example, the alkyl and alkylaryl sulfonates and sulfates and their sodium salts; polyhydroxy alcohols; and other types of surface-active agents, many of which are available in commerce. The surface-active agent, when used, normally comprises from 0.1% to 15% by weight of the fungicidal composition.

Dusts, which are free-flowing admixtures of the active ingredient with finely divided solids such as talc, clays, flours and other organic and inorganic solids which act as dispersants and carriers for the toxicant, are useful formulations for many applications.

Pastes, which are homogeneous suspensions of a finely divided solid toxicant in a liquid carrier such as water or oil, are employed for specific purposes. These formulations normally contain about 5% to about 95% of active ingredient by weight, and may also contain small amounts of a wetting, dispersing or emulsifying agent to facilitate dispersion. For application, the pastes are normally diluted and applied as a spray to the area to be affected.

EXAMPLES OF TYPICAL FORMULATIONS

    ______________________________________                                         EXAMPLES OF TYPICAL FORMULATIONS                                               ______________________________________                                         Ingredient            Weight %                                                 ______________________________________                                         Oil                                                                            Compound 1             1                                                       Oil solvent-heavy aromatic naphtha                                                                   99                                                       Total                 100                                                      Emulsifiable Concentrate                                                       Compound 2            50                                                       Kerosene              45                                                       Emulsifying agent (mixture of long                                             chain ethoxylated polyethers with                                              long chain sulfonate)  5                                                       Total                 100                                                      Emulsifiable Concentrate                                                       Compound 3            90                                                       Kerosene               5                                                       Emulsifying agent (mixture of long                                             chain ethoxylated polyethers with                                              long chain sulfonate)  5                                                       Total                 100                                                      ______________________________________                                         Dusts and/or Powders                                                           Ingredient       Wt. %     Wt. %   Wt. %                                       ______________________________________                                         Compound 1       0.5       50.0    90.0                                        Attapulgite Clay Powder                                                                         93.5      44.0    4.0                                         Sodium lignin sulfonate                                                                         5.0        5.0    5.0                                         Sodium dioctyl sulfosuccinate                                                                   1.0        1.0    1.0                                         Total            100.0     100.0   100.0                                       ______________________________________                                    

Other useful formulations for fungicidal applications include simple solutions of the active ingredient in a dispersant in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene and other organic solvents. Pressurized sprays, typically aerosols, wherein the active ingredient is dispersed in finely divided form as a result of vaporization of a low boiling dispersant solvent carrier, such as the Freons, may also be used.

The fungicidal compositions of this invention are applied to the plants in the conventional manner. Thus, the dust and liquid compositions can be applied to the plant by the use of power-dusters, boom and hand sprayers and spray dusters. The compositions can also be applied from airplanes as a dust or a spray because they are effective in low dosages. 

We claim:
 1. A compound having the structural formula ##STR27## wherein R is furfuryl or pyridyl, R₁ is selected from the group consisting of halogen, C₁ -C₃ alkoxy and C₁ -C₃ haloalkoxy, R₂ is hydrogen, and X is S or O; or a fungicidally acceptable organic or inorganic salt thereof.
 2. The compound of claim 1 wherein R is ##STR28## R₁ is --OCH₃ R₂ is --H and X is --O.
 3. A fungicidal composition comprising a fungicidally effective amount of a compound having the structural formula ##STR29## wherein R is furfuryl or pyridyl, R₁ is selected from the group consisting of halogen, C₁ -C₃ alkoxy and C₁ -C₃ haloalkoxy, R₂ is hydrogen, and X is S or O; or a fungicidally acceptable organic or inorganic salt thereof and an inert diluent carrier therefor.
 4. The method of controlling fungi comprising applying to the area where control is desired, a fungicidally effective amount of a compound having the formula ##STR30## wherein R is furfuryl or pyridyl, R₁ is selected from the group consisting of halogen, C₁ -C₃ alkoxy and C₁ -C₃ haloalkoxy, R₂ is hydrogen, and X is S or O; or a fungicidally acceptable organic or inorganic salt thereof.
 5. The compound of claim 4 wherein R is ##STR31## R₁ is --OCH₃, R₂ is --H and X is --O. 